Amphidinolide synthesis

From aryl halide 110 From alcohol 156 Protection 100, 101, 144 Amino acid from hydroxy acid 40 Amphidinolide synthesis 50,94 Anatoxin synthesis 82 Aromatic ring construction 171,191 Aromatic ring substitution 10,18,19,21, 48, 54, 65,69, 104, 108, 110, 111, 120, 122,138, 149, 164, 171, 174, 175, 190,205... 

Ishiyama, H., Ishibashi, M., and Kobayashi, J. (1996) Studies on ihe stereochemistry of amphidinolides synthesis of a diastereomer of the C1-C9 fragment of amphidinoUde C. Chem. Pharm. Bull., 44, 1819-1822. 

In some cases, if necessary, a C(3)-regioselective addition of cuprate can be accomplished by the use of a sterically demanding protecting group - such as an -OTr or -OMMTr group - on C(l), as described in the synthesis of the polypropionate segment present in (-)-amphidinolide P and (+)-amphidinolide K [54]. 

Scheme 38 Regioselective RCM of heptaene 193 in Maleczka s synthesis of the structure 195 proposed for amphidinolide A [96a]...

Scheme 39 Influence of a remote substituent on efficiency and stereochemistry of the RCM step in Fiirstner s total synthesis of amphidinolide T4 (199) [98a] and amphidinolide T3 (12-epf-199) [98b]...

In Ghosh s enantioselective total synthesis of the cytotoxic marine macrolide (+)-amphidinolide T1 (318) [143], the C1-C10 fragment 317 was constructed by CM of subunits 315 and 316 (Scheme 62). The reaction mediated by catalyst C (5 mol%) afforded in the first cycle an inconsequential 1 1 mixture of (E/Z)-isomeric CM products 317 in 60% yield, along with the homodimers of 315 and 316. The self-coupling products were separated by chromatography and exposed to a second metathesis reaction to provide olefins 317 in additional 36% yield [144]. 

Scheme 62 Efficient coupling of fragments 315 and 316 via CM in Ghosh s total synthesis of the cytotoxic marine macrolide amphidinolide T1 (318) [143]...

The Stille reaction has been successfully applied to a number of macrocyclic ring closures.207 In a synthesis of amphidinolide A, the two major fragments were coupled via a selective Stille reaction, presumably governed by steric factors. After deprotection the ring was closed by coupling the second vinyl stannane group with an allylic acetate.208... 

Entries 4 and 5 are examples of use of the Sakurai reaction to couple major fragments in multistage synthesis. In Entry 4 an unusual catalyst, a chiral acyloxyboronate (see p. 126) was used to effect an enantioselective coupling. (See p. 847 for another application of this catalyst.) Entry 5 was used in the construction of amphidinolide P, a compound with anticancer activity. 

Other procedures using TPAP/NMO/PMS/CH Cl include steps in the synthesis of (+)-altholactone (lactol to lactone) [78] antheliolide A [168] the AChE inhibitor (+)-arisugacin A and B (primary alcohol to aldehyde step also) [83] the marine macrolide amphidinolide T1 [169] the alkaloid (+)-batzelladine D cf. mech. 

The iron-catalyzed addition of Grignard reagents to propargylic epoxides developed by Furstner and Mendez allows one to prepare a yw-allenol, which is an important intermediate for the synthesis of a precursor of the amphidinolide X (Scheme 67). 

SCHEME 81. Synthesis of amphidinolide T1 via Pd-catalyzed acylation of an alkylzinc derivative... 

The amphidinolides are a class of structurally diverse and physiologically potent natural products. The key step in the total synthesis of enantiomerically-pure amphidinolide T l 3 recently reported (J. Am. Chem. Soc. 2004,126,998) by Timothy Jamison of , the Ni-mediated cyclization of 1 to 2, clearly illustrates the power of organometallic C-C bond formation in organic synthesis. 

Corey s asymmetric allylation methodology was utilized in the total synthesis of amphidinolide T3 (95), a marine natural product that exhibits significant antitumor properties37 (Scheme 3.1gg). The asymmetric allylation of the aldehyde 96 was carried out successfully with chiral allylborane reagent generated in situ from allyltributylstannane and (R,R)-82 to furnish the homoallylic alcohol desired (97) in 85% yield with excellent diastereoselectivity. Subsequent conversion of the alcohol to the tosylate ester followed by treatment with potassium hydroxide resulted in formation of the trisubstituted tetrahydrofuran 98. 

B. M. Trost, J. D. Chisholm, S. T. Wrobleski, and M. Jung, Ruthenium-catalyzed alkene-alkyne coupling Synthesis of the proposed structure of amphidinolide A, J. Am. Chem. Soc., 124 (2002) 1242-12421. 

In the laboratory of T.F. Jamison, the synthesis of amphidinolide T1 was accomplished utilizing a catalytic and stereoselective macrocyclization as the key step. ° The Myers asymmetric alkylation was chosen to establish the correct stereochemistry at the C2 position. In the procedure, the alkyl halide was used as the limiting reagent and almost two equivalents of the lithium enolate of the A/-propionyl pseudoephedrine chiral auxiliary was used. The alkylated product was purified by column chromatography and then subjected to basic hydrolysis to remove the chiral auxiliary. 

A convergent total synthesis of 15-membered macrolactone, (-)-amphidinolide P was reported by D.R. Williams and coworkers.In their approach, they utilized the Sakurai aiiyiation to introduce the C7 hydroxyl group and the homoallylic side chain. The transformation was effected by BF3-OEt2 at -78 °C to provide the homoallylic alcohol as a 2 1 mixture of diastereomers. The desired alcohol proved to be the major diastereomer, as it resulted from the Felkin-Ahn controlled addition of the allylsilane to the aldehyde. The minor diastereomer was converted into the desired stereoisomer via a Mitsunobu reaction. 

Williams, D. R., Meyer, K. G. Palladium-Induced Cyclizations for the Synthesis of cis-2,5-Disubstituted-3-methylenetetrahydrofurans Studies of the C7-C22 Core of Amphidinolide K. Org. Lett. 1999, 1, 1303-1305. 

The synthesis of the 36-membered macrolide dermostatin A (42), carried out by Rychnovsky, is remarkable for the complexity of this natural product and its acid- and light-sensitivity (Scheme 5.4.10). i Several approaches to the synthesis of amphidinolides also make use of alkenyl-alkenyl Stille coupling... 

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